The long-term goal of this project is to determine the neurobiological mechanisms that underlie effects of estrogen on the adult hypothalamo-pituitary-adrenal (HPA) axis. HPA axis activation in mammals is a basic response to environmental perturbations that threaten homeostasis and such responses, although beneficial in the short-term, have deleterious consequences under chronic conditions. Prolonged elevations of adrenal glucocorticoids (GCs) are neuroendangering and alter behaviors. Moreover, a dysregulation of the HPA activity accompanies neuropsychiatric disorders. In rodents, females show a more robust HPA axis response to stress than do males, partly because of sex-differences in circulating estradiol (E2) levels. Thus, the overarching postulate of this application is that individual differences in adult stress-responses arise from differential E actions on the stress-circuitry. Our studies focus predominantly on estrogen receptor beta (ER?). Rodent studies show that the alpha form of ER (ER?) increases adrenal corticosterone (CORT) and pituitary adrenocorticotropic hormone (ACTH) response to stressors whereas activation of ER? inhibits HPA activity. Importantly, ER? is highly expressed in neurons of the PVN of both male and female mice, allows integration of gonadal hormone levels with stress-related inputs. Using novel transgenic mouse models, we will identify stress responsive ER?-ergic neural circuitry of the mouse hypothalamus, and determine if activation of PVN ER? reduces HPA drive through OTergic pathways. Specific aim 1 will assess populations of ER? and ER? neurons that are incorporated into the stress circuitry of the mouse brain. Aim 2 will test the hypothesis that activation of ER? in male and female PVN neurons inhibits HPA axis function through 1) synaptic connections between ER? and CRH neurons or 2) through reciprocal projections to the Bed n. of the Stria Terminalis (BST) or medial Amygdala (mAmg). Aim 3 will elucidate molecular changes and sex differences that occur in PVN ER? neurons in response to stress or ER (? / ?) agonist treatment. Aim 4 will directly test whether OT is requird for ER? regulation of PVN function. The results of these studies will provide novel insight into the role played by PVN ER? neurons in controlling hypophysiotrophic function with hopes of identifying novel targets for therapeutic approaches to treating stress and associated neurological deficits.